Protease activated receptor-2 (PAR-2) belongs to a new family of G protein-coupled receptors which are activated by proteolytic cleavage at the amino-terminus exposing a tethered ligand which binds to an as yet unidentified region of the receptor. In this study, we describe the development of a PAR-2 gene-disrupted mouse (-/-) by homologous recombination in embryonic stem cells, and demonstrate, for the first time, in vivo evidence of PAR-2 function. PAR-2 -/- mice appear normal and proceed to adulthood. PAR-2 deficiency was confirmed by Northern analyses of harvested tissues and cultured cells. Loss of receptor function was determined by the absence of the hypotensive response to an intravenous injection of the murine PAR-2 activating peptide, SLIGRI [SEQ. ID. NO:1]. Most interestingly, PAR-2 -/- mice had significantly less edema associated with carageenin induced paw inflammation. This report represents the first in vivo evidence that PAR-2 may play a role in the acute phase of the inflammatory response.